Leucine-rich glioma inactivated 3: Integrative analyses support its role in the cytokine network

Abstract

Leucine-rich glioma inactivated (LGI)3 is a secreted protein member of LGI family. We previously repo rted that LGI3 was upregulated in adipose tissues from obese mice and suppressed adipogenesis through its receptor, a disintegrin and metalloproteinase domain-containing protein 23 (ADAM23). We demonstrated that LGI3 regulated tumor necrosis factor-α and adiponectin, and proposed that LGI3 may be a pro-inflammatory adipokine involved in adipose tissue inflammation. In this study, we analyzed adipokine and cytokine profiles in LGI3 knockout mice and demonstrated that multiple factors were increased or decreased in the adipose tissues and plasma of the LGI3 knockout mice. Phosphoprotein array analysis revealed increases in the phosphorylation levels of Akt, AMP-activated protein kinase (AMPK), Bad, extracellular signal-regulated kinase (Erk)1/2, glycogen synthase kinase 3α (GSK3α), phosphatase and tensin homolog (PTEN) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in the LGI3treated 3T3-L1 pre-adipocytes. Treatment with LGI3 increased the expression of various inflammatory genes in pre-adipocytes, adipocytes and macrophages. Integrative functional enrichment analysis for all LGI3-regulated gene products suggested their involvement in a number of biological processes, including cancer, inflammatory response, response to wounding, as well as cell proliferation and differentiation. Protein interaction network analysis of LGI3-regulated gene products revealed that 94% of the gene products formed a cluster of interaction networks. Taken together, these results support the critical involvement of LGI3 in the cytokine network by interplaying with multiple adipokines, cytokines and signaling proteins.

Leucine-rich glioma inactivated 3: integrative analyses support its prognostic role in glioma

“…We reported that a majority of LGI3-regulated gene products (94%, 45/48 genes) formed a cluster of protein–protein interaction network 18. Protein–protein interaction network analysis of LGI3- and glioma-regulated genes showed that 11/13 genes of glioma-altered and LGI3-regulated genes participated in a cluster of interaction network (Figure 2B).…”

“…LGI protein members were shown to be differentially expressed in various types of tumor cells (glioma, neuroblastoma, melanoma, colon and breast cancers), and LGI3 was the only LGI family member expressed at significant levels in glioma, melanoma and neuroblastoma 11. This study was prompted by our previous reports supporting the roles of LGI3 as a multifunctional cytokine4–9 and the predicted association of LGI3 with cytokine network in cancer 18…”

“…LGI3 downregulated PPARγ and suppressed adipocyte differentiation through ADAM23 4. LGI3-treated preadipocytes showed the regulation of multiple signaling proteins (upregulated: Akt, AMPK, Erk1/2, PTEN; downregulated: 4E-BP1, Bad, GSK3α) 18. Since ADAM22 and ADAM23 are abundant in brain,21 it remains to investigate whether LGI3-induced intracellular signaling pathways through these receptors are relevant and dysregulated in glioma cells.…”

“…LGI3 was reported to transduce intracellular signals through proteins crucially involved in cancers including ADAM23, Akt, β-catenin, focal adhesion kinase, MDM2, p53, NF-κB and microphthalmia-associated transcription factor (MITF) 3,5,6,9,35–38. Perturbation of these proteins by downregulated LGI3 and its receptors in glioma may account for the role of LGI3 in pathogenesis and prognosis in glioma and other cancers 18. Our additional analysis using The Cancer Genome Atlas (TCGA) databases showed significant positive prognostic association of LGI3 expression with lower grade glioma ( P =0.05, N=206) and association of ADAM22 with glioblastoma multiforme ( P =0.009, N=542) and lower grade gliomas ( P =0.047, N=206; data not shown).…”

Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis

“…LGI3, a secreted protein member of leucine-rich glioma inactivated (LGI) family, is predominantly expressed in the brain, skin, and adipose tissues, exerting roles as a multifunctional cytokine [ 15 ]. Studies have revealed that low expression levels of LGI3 are obviously associated with poor prognosis of glioma [ 16 ]. Collectively, the clinical value of these DEGs needs to be further explored.…”